骨髓性肿瘤中的胚系 DDX41 基因突变:目前的临床和分子认识。

IF 3.1 3区 医学 Q2 HEMATOLOGY
Junichiro Kida, Timothy M Chlon
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引用次数: 0

摘要

综述目的:DDX41 基因突变是导致成人髓样肿瘤种系易感性的最常见原因。其独特的突变情况和临床特征表明其具有独特的分子发病机制,但由于 DDX41 的功能繁多,人们对 DDX41 突变致病的确切机制知之甚少。在本综述中,我们将更新 DDX41 的已知功能,介绍其独特的临床特征和治疗注意事项,并总结目前对该病分子发病机制的理解:大型队列研究显示,种系 DDX41 变异是杂合的,且主要是功能缺失。半数以上的患者在发病时存在对侧 DDX41 等位基因的获得性突变,通常为 R525H,发病年龄在 50 岁以后。DDX41 对造血至关重要,在 RNA 代谢和先天性免疫感应方面具有多功能。实验模型表明,R 环解析和核糖体生物发生缺陷下游的先天性免疫激活在发病机制中起着关键作用。摘要:虽然深入研究揭示了基因型与表型之间的密切关系,但最佳治疗方法和长期疗效仍未确定。目前迫切需要在单细胞和多组学水平上对患者进行仔细检查,并推进动物和人体实验模型的发展,以全面阐明分子发病机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Germline DDX41 mutations in myeloid neoplasms: the current clinical and molecular understanding.

Purpose of review: DDX41 mutations are the most common cause of germline predisposition to adult-onset myeloid neoplasms. The unique mutational landscape and clinical features indicate a distinct molecular pathogenesis, but the precise mechanism by which DDX41 mutations cause disease is poorly understood, owing to the multitude of DDX41 functions. In this review, we will update DDX41's known functions, present unique clinical features and treatment considerations, and summarize the current understanding of the molecular pathogenesis of the disease.

Recent findings: Large cohort studies have revealed that germline DDX41 variants are heterozygous and predominantly loss-of-function. Acquired mutation of the contralateral DDX41 allele, typically R525H, is present in more than half of patients at disease onset, which occurs after age 50. DDX41 is essential for hematopoiesis and has versatile functions in RNA metabolism and innate immune sensing. Experimental models have suggested that innate immune activation downstream of defects in R-loop resolution and ribosome biogenesis plays a key role in the pathogenesis.

Summary: While intensive investigations unveiled a strong genotype-phenotype relationship, the optimal therapeutic approach and long-term outcome are undefined. There is an urgent need to scrutinize the patients at single cell and multiomics level and to advance experimental animal and human models to fully elucidate the molecular pathogenesis.

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来源期刊
CiteScore
6.60
自引率
3.10%
发文量
78
审稿时长
6-12 weeks
期刊介绍: ​​​​​​​​Current Opinion in Hematology is an easy-to-digest bimonthly journal covering the most interesting and important advances in the field of hematology. Its hand-picked selection of editors ensure the highest quality selection of unbiased review articles on themes from nine key subject areas, including myeloid biology, Vascular biology, hematopoiesis and erythroid system and its diseases.
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